Hepatitis C virus is both difficult to treat and a significant cause of morbidity and mortality. It is not understood how hepatitis C establishes infection nor how some patients clear infection. To this end 83 humans exposed to hepatitis C were studied in protocol 00-DK-0221. The immune response (both antibody and T cell) was closely followed and is being characterized. The study is in collaboration with Dr. Rehermann. As an extension of this 28 patients with acute hepatitis C have been followed and treated as indicated. Their clinical course, virological parameters, and T cell responses have been carefully defined. This is in collaboration with Dr. Rehermann. All patients except three have cleared virus, either spontaneously or with treatment. Two of those who did not clear relapsed after therapy and are co-infected with HIV. The third non-responder started treatment in the chronic phase when response rates are lower than during the acute phase. [unreadable] [unreadable] To further understand the virological determinants of infection and the development of chronicity, the hepatitis C virus sequence in the early stages of infection is being determined from the same patients. In particular the sequencing effort is focused on the viral sequence before and after treatment, in the two patients who were HIV positive and relapsed.[unreadable] [unreadable] Once chronicity has been established treatment response rates decrease significantly. One of the hallmarks of the hepatitis C virus is its sequence diversity, which is used to classify hepatitis C into different genotypes. Different genotypes have different response rates to treatment. Response rates are typically higher in genotype 2/3. Protocol 03-DK-0136 studies the response of patients with chronic hepatitis C, genotypes 2 or 3, to a decreased dose of pegylated interferon in combination with ribavirin. 30 patients were treated with low-dose peginterferon alfa-2a (90 g/week) and 23 patients with standard doses (180 g/week) for 24 weeks in combination with 800 mg/day of ribavirin. Patients who failed treatment were offered 48 weeks of standard-dose treatment. Viral and serum IP-10 levels were measured and early viral kinetic parameters were calculated. Sustained virological response was achieved in 68% of the low-dose and 84% of the standard-dose treated patients (per-protocol, p=0.81 for non-inferiority). Retreatment was successful in all patients who tolerated full dose and duration. The standard-dose group had a greater first phase decline of the viral levels and faster time to negativity. The second phase slope was not affected by peginterferon dose. Although fatigue and general feeling during treatment were worse for standard dose, hematologic toxicity and depression did not differ between groups. Treatment with a lower dose of peginterferon is associated with some symptomatic benefit but the response is not equivalent to standard dosing. [unreadable] [unreadable] A second type of chronic hepatitis studied is hepatitis D. Hepatitis D is the most aggressive form of viral hepatitis as well as the most difficult to treat. Interferon therapy is the standard approach. Patients are typically treated for 6 months to a year. Relapse after cessation of therapy is the norm. In protocol 01-DK0247 patients are treated with peginterferon for 5 years. The dose is titrated to maintain normal ALT and minimize side effects. Patients are evaluated before initiating therapy, and after 1, 3, and 5 years. Patients are excluded if they do not meet protocol-defined criteria for response at the 1 year evaluation. Enrollment was planned for 10 - 20 patients. Thirteen patients have been enrolled, and of the 12 who have had one-year evaluations 10 have met the protocol definition of response. Six patients have had their end of 3 year evaluation, 5 have been excluded (one non-compliant, one lost to follow up and only a partial responder, one non-responder, and two deaths), three have developed antibody to HBs, a protocol end point. The primary end point of the study is the evaluation after three years although it is planned to treat patients for 5 years.